Method for producing a spirooxindole derivative

ABSTRACT

The present disclosure provides a method for efficiently producing and providing compounds having a spirooxindole skeleton, for example compounds having a spirooxindole skeleton and having antitumor activity that inhibit the interaction between Mdm2 protein and p53 protein, or intermediates thereof, using an asymmetric catalyst. Compounds having optically active tricyclic dispiroindole skeletons are obtained through catalytic asymmetric 1,3-dipolar cycloaddition reaction using ketimine as a reaction substrate and using a chiral ligand and a Lewis acid.

This application is a divisional application of U.S. application Ser.No. 16/031,165, filed Jul. 10, 2018, which is a divisional applicationof U.S. application Ser. No. 14/916,677, filed Mar. 4, 2016, now U.S.Pat. No. 10,030,028, entitled “Method for Producing a SpirooxindoleDerivate,” which is a national stage application under 35 U.S.C. 371 ofInternational Application No. PCT/JP2014/073233, filed Sep. 3, 2014,entitled “Method for Producing Spirooxindole Derivative,” which claimspriority to Japanese Patent Application No. 2013-182928, filed Sep. 4,2013.

TECHNICAL FIELD

The present invention relates to a method for producing a pyrrolidinecompound having a spirooxindole structure.

BACKGROUND ART

A method which involves using, as a reaction substrate, aldiminesynthesized from an aldehyde and an amine as starting materials tosynthesize a racemic compound through a 1,3-dipolar cycloadditionreaction in the presence or absence of a catalyst that promotes thereaction is known as a method for synthesizing a pyrrolidine compoundhaving a bicyclic spirooxindole structure (Non Patent References 1 to4). The obtained racemic compound can be resolved using a chiral columnbased on a technique such as HPLC or supercritical fluid chromatography(SFC) to separate a desired optically active form.

An asymmetric synthesis method through a 1,3-dipolar cycloadditionreaction using a chiral element has been reported as a method forstereoselectively synthesizing the compound mentioned above (Non PatentReferences 5 and 6). In addition, a method for producing a pyrrolidinecompound having a tricyclic dispirooxindole structure through a1,3-dipolar addition reaction using, as a reaction substrate, ketiminesynthesized with an amine and a ketone as starting materials has alsobeen reported (Patent Reference 1).

Meanwhile, as for catalytic asymmetric synthesis methods of the compoundmentioned above, a large number of studies have been made on catalyticasymmetric 1,3-dipolar cycloaddition reactions using aldimine as areaction substrate (Non Patent References 7 to 18). Nonetheless, noreport has been made on the synthesis of a tricyclic dispiroindole usingketimine with a ketone and an amine as reaction substrates.

CITATION LIST Patent References

-   Patent Reference 1: WO2012/121361

Non Patent References

-   Non Patent Reference 1: Jorgensen, K. A. et al., Org. Lett. 2005,    21, 4569-   Non Patent Reference 2: Jorgensen, K. A. et al., Chem. Rev. 1998,    98, 863-   Non Patent Reference 3: Grigg, R. et al., Tetrahedron, 1992, 48,    10431-   Non Patent Reference 4: Schreiber, S. L. et al., J. Am. Chem. Soc.    2003, 125, 10174-   Non Patent Reference 5: Carretero, J. C. et al., Tetrahedron, 2007,    63, 6587-   Non Patent Reference 6: Wang, S. et al., J. Am. Chem. Soc., 2005,    127, 10130-   Non Patent Reference 7: Wang, S. et al., J. Med. Chem. 2006, 49,    3432-   Non Patent Reference 8: Williams, R. M. et al., J. Am. Chem. Soc.    2000, 122, 5666-   Non Patent Reference 9: Gong, L.-Z. et al., J. Am. Chem. Soc., 2009,    131, 13819-   Non Patent Reference 10: Gong, L.-Z. et al., Org. Lett., 2011, 13,    2418-   Non Patent Reference 11: Gong, L.-Z. et al., Chem. Eur. J., 2012,    18, 6885-   Non Patent Reference 12: Waldmann, H. et al., Nat. Chem., 2010, 2,    735-   Non Patent Reference 13: Waldmann, H. et al., Tetrahedron, 2011, 67,    10195-   Non Patent Reference 14: Wang, C.-J. et al., Org. Biomol. Chem.,    2011, 9, 1980-   Non Patent Reference 15: Arai, T. et al., Chem. Eur. J., 2012, 18,    8287-   Non Patent Reference 16: Amedohkouh, M. et al., Tetrahedron    Asymmetry, 2005, 8, 1411-   Non Patent Reference 17: Cordova, A. et al., Chem. Comm. 2006, 460-   Non Patent Reference 18: Ma, J. A. et al., Org. Lett. 2007, 9, 923

SUMMARY OF INVENTION Technical Problem

The present invention is intended to provide a method for efficientlyproducing and providing a compound having a spirooxindole skeleton, forexample, a compound having a spirooxindole skeleton and having antitumoractivity that inhibits the interaction between Mdm2 protein and p53protein, or an intermediate thereof using an asymmetric catalyst.

Solution to Problem

The present inventors have conducted diligent studies and consequentlyestablished a method for efficiently synthesizing a compound having anoptically active tricyclic dispiroindole skeleton by screening for achiral ligand that promotes a catalytic asymmetric 1,3-dipolarcycloaddition reaction using ketimine as a reaction substrate, and aLewis acid serving as a central metal thereof, and the optimum reactionconditions.

Specifically the present invention relates to the following (1) to (20):

(1) A Method for Reacting a Compound Represented by Formula (I):

a compound represented by formula (II):

and a compound represented by formula (III):

in a solvent using an asymmetric catalyst to stereoselectively produce acompound represented by formula (IV) or a salt thereof:

wherein

R¹ represents a hydrogen atom, a C₁-C₆ alkylcarbonyl group optionallyhaving 1 to 3 substituents independently selected from group A below, ora C₁-C₆ alkoxycarbonyl group optionally having 1 to 3 substituentsindependently selected from group A below,

R² represents a 5- or 6-membered heteroaryl group having, in the ring, 1to 3 heteroatoms independently selected from the group consisting of anitrogen atom, an oxygen atom and a sulfur atom, a phenyl group, a C₃-C₆cycloalkyl group, or a C₃-C₆ cycloalkenyl group, wherein

the 5- or 6-membered heteroaryl group, the phenyl group, the C₃-C₆cycloalkyl group, and the C₃-C₆ cycloalkenyl group each optionally have1 to 3 substituents independently selected from the group consisting ofa halogen atom, a vinyl group, an ethynyl group, a cyano group, ahydroxy group, an amino group, a carboxy group, an aminocarbonyl group,a C₁-C₆ alkyl group optionally having 1 to 3 substituents independentlyselected from group A below, a C₃-C₄ cycloalkyl group optionally having1 to 3 substituents independently selected from group A below, a C₁-C₆alkoxy group optionally having 1 to 3 substituents independentlyselected from group A below, a C₃-C₄ cycloalkoxy group optionally having1 to 3 substituents independently selected from group A below, a C₁-C₆alkylamino group optionally having 1 to 3 substituents independentlyselected from group A below, a di-C₁-C₆ alkylamino group optionallyhaving 1 to 3 substituents independently selected from group A below, a4- to 7-membered saturated heterocyclic group containing one nitrogenatom in the ring and optionally having 1 to 3 substituents independentlyselected from group B below, a C₁-C₆ alkoxycarbonyl group optionallyhaving 1 to 3 substituents independently selected from group A below, aC₃-C₄ cycloalkoxycarbonyl group optionally having 1 to 3 substituentsindependently selected from group A below, a C₁-C₆ alkylaminocarbonylgroup optionally having 1 to 3 substituents independently selected fromgroup A below, and a C₃-C₄ cycloalkylaminocarbonyl group optionallyhaving 1 to 3 substituents independently selected from group A below,

R³ and R⁴ each independently represent a C₁-C₆ alkyl group optionallyhaving 1 to 3 substituents independently selected from group C below, or

R³ and R⁴ optionally together form a C₄-C₆ cycloalkyl ring, atetrahydrofuran ring, a tetrahydropyran ring, or a piperidine ring,wherein

the C₄-C₆ cycloalkyl ring, the tetrahydrofuran ring, the tetrahydropyranring, and the piperidine ring each optionally have 1 to 8 substituentsindependently selected from group D below,

R⁵ represents a C₁-C₆ alkoxy group optionally having 1 to 3 substituentsindependently selected from group E below, a C₃-C₈ cycloalkoxy groupoptionally having 1 to 3 substituents independently selected from groupE below, a C₂-C₆ alkenyloxy group, or —NR⁵¹R⁵²,

R⁵¹ and R⁵² each independently represent a hydrogen atom, a C₁-C₆ alkylgroup optionally having 1 to 3 substituents independently selected fromgroup E below, a C₃-C₈ cycloalkyl group optionally having 1 to 3substituents independently selected from group E below, or a 3- to6-membered saturated heterocyclic group having, in the ring, oneheteroatom independently selected from the group consisting of anitrogen atom, an oxygen atom and a sulfur atom and optionally having 1to 3 substituents independently selected from group E below, and

ring Z represents a benzene ring optionally having 1 to 4 substituentsindependently selected from group E below, a pyridine ring optionallyhaving 1 to 3 substituents independently selected from group E below, ora pyrimidine ring optionally having 1 or 2 substituents independentlyselected from group E below:

group A: a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, an aminogroup, and a phenyl group,

group B: a C₁-C₆ alkyl group and a hydroxy group

group C: a halogen atom, a hydroxy group, a phenyl group, a pyridylgroup, and an amino group

group D: a halogen atom and a C₁-C₆ alkyl group optionally having 1 to 3halogen atoms, and

group E: a halogen atom, a hydroxy group, a vinyl group, an ethynylgroup, a cyano group, a C₁-C₆ alkoxy group, an aminocarbonyl group, anda C₁-C₆ alkyl group optionally having 1 to 3 halogen atoms.

(2) A method for reacting a compound represented by formula (I):

and a compound represented by formula (V):

in a solvent using an asymmetric catalyst to stereoselectively produce acompound represented by formula (IV) or a salt thereof:

wherein R¹, R², R³, R⁴, R⁵, and Z are as defined in (1).

(3) A method according to (1) or (2), wherein the asymmetric catalyst isa catalyst prepared from a Lewis acid and a chiral ligand, wherein theLewis acid is a Lewis acid selected from the group consisting of aZn(II) Lewis acid, a Ag(I) Lewis acid, a Ni(II) Lewis acid, a Co(II)Lewis acid, a Ru(I) Lewis acid, a Cu(I) Lewis acid, and a Cu(II) Lewisacid, and the chiral ligand is a chiral ligand selected from the groupconsisting of a compound represented by the following formula (VI):

a compound represented by the following formula (VII):

a compound represented by the following formula (VIII):

a compound represented by the following formula (IX):

a compound represented by the following formula (X):

a compound represented by the following formula (XI):

and a compound represented by the following formula (XII):

wherein

R⁶ represents a phenyl group optionally having 1 to 3 substituentsindependently selected from group F below,

ring Y represents a benzene ring, a cyclohexane ring, or a dioxolanering optionally having 1 to 4 halogen atoms,

R⁷ represents a phenyl group optionally having 1 to 3 substituentsindependently selected from group G below, or a furanyl group optionallyhaving 1 to 3 substituents independently selected from group G below,

R⁸ represents a hydrogen atom or a C₁-C₆ alkoxy group,

R⁹ represents a C₁-C₆ alkoxy group, or

two R⁹ moieties optionally together form a 7- to 12-memberedheterocyclic ring containing two oxygen atoms in the ring,

X represents CH, CR¹⁰, or a nitrogen atom, wherein

R¹⁰ represents a C₁-C₆ alkoxy group,

V represents a phenyl group having one P(R¹¹)₂ or PH(O)R¹², wherein

R¹¹ represents a C₁-C₆ alkyl group, a cyclohexyl group, or a phenylgroup optionally having two trifluoromethyl groups, and

R¹² represents a C₁-C₆ alkyl group or a phenyl group, W represents aC₁-C₆ alkylthio group, a dihydrooxazolyl group optionally having oneC₁-C₆ alkyl group, CH(CH₃)P(R¹³)₂, or CHR¹⁴R¹⁵, wherein

R¹³ represents a cyclohexyl group, a C₁-C₆ alkyl group, or a phenylgroup optionally having 1 or 2 substituents independently selected fromgroup H below,

R¹⁴ represents a phenyl group optionally substituted by one P(R¹⁶)₂,

R¹⁵ represents a C₁-C₆ alkyl group or a di-C₁-C₆ alkylamino group, and

R¹⁶ represents a phenyl group or a cyclohexyl group,

U represents any one of the following U^(a) to U^(d):

R¹⁷ represents a phenyl group optionally having 1 to 3 substituentsindependently selected from group F below,

R¹⁸ represents a C₁-C₆ alkyl group or a phenyl group,

R¹⁹ represents a hydrogen atom or a C₁-C₆ alkyl group, and

R²⁰ and R²¹ each independently represent a C₁-C₆ alkyl group:

group F: a C₁-C₆ alkyl group and a C₁-C₆ alkoxy group,

group G: a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, and a di-C₁-C₆alkylamino group, and

group H: a C₁-C₆ alkyl group and a C₁-C₆ alkyl group optionally havingthree halogen atoms.

(4) A method according to any one of (1) to (3), wherein the Lewis acidused in the preparation of the asymmetric catalyst is a Cu(I) Lewis acidor a Cu(II) Lewis acid.

(5) A method according to any one of (1) to (4), wherein the Lewis acidused in the preparation of the asymmetric catalyst is a Lewis acidselected from the group consisting of CuOAc, CuCl, CuBr, CuI, CuOTf,CuPF₆, CuBF₄, Cu(OAc)₂, Cu(OTf)₂, and CuSO₄.

(6) A method according to any one of (1) to (5), wherein the chiralligand used in the preparation of the asymmetric catalyst is a chiralligand selected from the group consisting of a compound represented byformula (V), a compound represented by formula (VI), a compoundrepresented by formula (VII), a compound represented by formula (VIII),a compound represented by formula (IX), a compound represented byformula (X), and a compound represented by formula (XI),

wherein

R⁶ represents a phenyl group optionally having 1 to 3 substituentsindependently selected from the group consisting of a methyl group, at-butyl group, and a methoxy group,

ring Y represents a benzene ring, a cyclohexane ring, or a dioxolanering,

R⁷ represents a phenyl group or a furanyl group, wherein

the phenyl group and the furanyl group each optionally have 1 to 3substituents independently selected from the group consisting of amethyl group, a t-butyl group, and a methoxy group,

R⁸ represents a hydrogen atom or a methoxy group,

R⁹ represents a methoxy group, or,

two R⁹ moieties optionally together form a 9-membered heterocyclic ringcontaining two oxygen atoms in the ring,

X represents CH, CR¹⁰, or a nitrogen atom,

R¹⁰ represents a methoxy group,

V represents P(R¹¹)₂, wherein

R¹¹ represents a phenyl group optionally having two trifluoromethylgroups,

W represents a t-butylthio group, a dihydrooxazolyl group optionallysubstituted by one isopropyl group, or CH(CH₃)P(R¹³)₂, wherein

R¹³ represents a phenyl group optionally having 1 or 2 methyl groups,

U represents U^(a) or U^(d) mentioned above,

R¹⁷ represents a phenyl group,

R¹⁸ represents an isopropyl group, a t-butyl group, or a phenyl group,

R¹⁹ represents a hydrogen atom, and

R²⁰ and R²¹ each independently represent a methyl group or a t-butylgroup.

(7) A method according to any one of (1) to (6), wherein the chiralligand used in the preparation of the asymmetric catalyst is a chiralligand selected from the following group:

(8) A method according to any one of (1) to (7), wherein the solventused in the reaction is one or more solvents selected from the groupconsisting of N,N-dimethylacetamide, tetrahydrofuran, dimethoxyethane,2-propanol, toluene, and ethyl acetate.

(9) A method according to any one of (1) to (8), wherein the compoundproduced or salt thereof has the following configuration:

wherein R¹, R², R³, R⁴, R⁵, and Z are as defined in (1).

(10) A method according to any one of (1) to (9), wherein R₁ is ahydrogen atom.

(11) A method according to any one of (1) to (10), wherein in formula(I),

ring Z is a benzene ring optionally having 1 to 4 halogen atoms.

(12) A method according to any one of (1) to (11), wherein in formula(I) or formula (IV),

R² is a pyridyl group optionally having 1 to 3 halogen atoms, or aphenyl group optionally having 1 to 3 halogen atoms.

(13) A method according to any one of (1) to (12), wherein in formula(II) or formula (V),

R³ and R⁴ each represent a methyl group, or R³ and R⁴ together form acyclopentane ring, a cyclohexane ring, or a tetrahydropyran ring,wherein

the cyclopentane ring, the cyclohexane ring, and the tetrahydropyranring each optionally have 1 to 4 C₁-C₆ alkyl groups on the ring.

(14) A method according to any one of (1) to (13), wherein in formula(III) or formula (V),

R⁵ is a substituent represented by the following:

(15) A method according to any one of (1) to (13), wherein in formula(III) or formula (V),

R⁵ is a C₁-C₆ alkoxy group.

(16) A method for hydrolyzing a compound or a salt thereof producedusing a method according to (15) to produce a compound represented bythe following formula (XIV) or a salt thereof:

and condensing the compound or the salt with a compound represented byNHR²²R²³ to produce a compound represented by the following formula (XV)or a salt thereof:

wherein

R¹, R², R³, R⁴, and Z are as defined in any one of (1) to (13), and

R²² and R²³ each independently represent a hydrogen atom, a C₁-C₆ alkylgroup optionally having 1 to 3 substituents independently selected fromgroup I below, a C₁-C₆ alkylsulfonyl group optionally having 1 to 3substituents independently selected from group I below, a C₃-C₆cycloalkyl group optionally having 1 to 3 substituents independentlyselected from group I below, a 3- to 6-membered saturated heterocyclicgroup having, in the ring, one heteroatom independently selected fromthe group consisting of a nitrogen atom, an oxygen atom and a sulfuratom and optionally having 1 to 3 substituents independently selectedfrom group I below, a phenyl group optionally having 1 to 3 substituentsindependently selected from group I below, or a 5- or 6-memberedheteroaryl group having, in the ring, 1 to 3 heteroatoms independentlyselected from the group consisting of a nitrogen atom, an oxygen atomand a sulfur atom and optionally having 1 to 3 substituentsindependently selected from group I below, or

R²² and R²³ optionally together form a piperazine ring optionally having1 to 3 substituents independently selected from group I below:

group I: a halogen atom, a hydroxy group, an oxo group, a carboxy group,a formyl group, an amino group, an aminocarbonyl group, a cyano group, aC₁-C₆ alkylamino group, a C₁-C₆ alkylsulfonyl group, a C₁-C₆alkylsulfonylamide group, a C₁-C₆ alkyl group optionally having 1 to 3substituents independently selected from group J below, a C₁-C₆ alkoxygroup optionally having 1 to 3 substituents independently selected fromgroup J below, a C₁-C₆ alkylcarbonyl group optionally having 1 to 3substituents independently selected from group J below, a C₃-C₆cycloalkylcarbonyl group optionally having 1 to 3 substituentsindependently selected from group J below, a C₄-C₆ cycloalkyl groupoptionally having 1 to 3 substituents independently selected from groupJ below, a C₁-C₆ alkoxycarbonyl group optionally having 1 to 3substituents independently selected from group J below, a piperidinylgroup optionally having 1 to 3 substituents independently selected fromgroup J below, a pyrrolidinyl group optionally having 1 to 3substituents independently selected from group J below, a piperazinylgroup optionally having 1 to 3 substituents independently selected fromgroup J below, a phenyl group optionally having 1 to 3 substituentsindependently selected from group J below, a tetrazolyl group, anazetidinyl group optionally having 1 to 3 substituents independentlyselected from group J below, a morpholino group optionally having 1 to 3substituents independently selected from group J below, adihydropyrazolyl group optionally having 1 to 3 substituentsindependently selected from group J below, and an oxadiazolyl group, and

group J: a halogen atom, a hydroxy group, an amino group, a carboxygroup, an aminocarbonyl group, a phenyl group, a C₁-C₆ alkyl group, aC₁-C₆ alkylamino group, a di-C₁-C₆ alkylamino group, a C₁-C₆alkylcarbonyl group, a C₃-C₆ cycloalkyl group, a C₁-C₆ alkylsulfonylgroup, and a C₁-C₆ alkylsulfonylamide group.

(17) A method according to (16), wherein

R²² represents a hydrogen atom, and

R²³ is a substituent represented by the following:

(18) A method for reacting

a compound represented by formula (XVI):

a compound represented by formula (XVII):

and a compound represented by formula (XVIII):

in a solvent using an asymmetric catalyst prepared from a Lewis acidselected from the group consisting of a Cu(I) Lewis acid and a Cu(II)Lewis acid and a chiral ligand selected from the following group:

to stereoselectively produce a compound represented by formula (XIX) ora salt thereof:

wherein

M represents a nitrogen atom or CH,

L represents a single bond, an oxygen atom, CH₂, or C(CH₃)₂, and

R⁵³ represents a C₁-C₆ alkyl group.

(19) A method for reacting a compound represented by formula (XVI):

and a compound represented by formula (XX):

in a solvent using an asymmetric catalyst prepared from a Lewis acidselected from the group consisting of a Cu(I) Lewis acid and a Cu(II)Lewis acid and a chiral ligand selected from the following group:

to stereoselectively produce a compound represented by formula (XIX) ora salt thereof:

wherein

M, L, and R⁵³ are as defined in 18.

(20) A method for hydrolyzing a compound or a salt thereof producedusing a method according to (18) or (19) to produce a compoundrepresented by the following formula (XXI) or a salt thereof:

and condensing the compound or the salt with a compound represented bythe following formula:

to produce a compound represented by the following formula (XXII) or asalt thereof:

whereinM and L are as defined in (18) or (19).

Advantageous Effects of Invention

According to the present invention, a compound having a spirooxindoleskeleton, for example, a compound having a spirooxindole skeleton andhaving antitumor activity that inhibits the interaction between Mdm2protein and p53 protein can be stereoselectively synthesized in anefficient and inexpensive manner.

DESCRIPTION OF EMBODIMENTS

In the present invention, a “halogen atom” is a fluorine atom, achlorine atom, a bromine atom, or an iodine atom.

In the present invention, a “C₁-C₆ alkyl group” refers to a linear orbranched alkyl group having 1 to 6 carbon atoms and is a methyl group,an ethyl group, a propyl group, an isopropyl group, a butyl group, anisobutyl group, a s-butyl group, a t-butyl group, a pentyl group, anisopentyl group, a 2-methylbutyl group, a neopentyl group, a1-ethylpropyl group, a hexyl group, an isohexyl group, or a4-methylpentyl group.

In the present invention, a “C₃-C₆ cycloalkyl group” is a cyclopropylgroup, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

In the present invention, a “C₃-C₄ cycloalkyl group” is a cyclopropylgroup or a cyclobutyl group.

In the present invention, a “C₁-C₆ alkoxy group” refers to a group inwhich a C₁-C₆ alkyl group mentioned above is substituted by an oxygroup, and is a methoxy group, an ethoxy group, a propoxy group, anisopropoxy group, a butoxy group, an isobutoxy group, a s-butoxy group,a t-butoxy group, a pentoxy group, an isopentoxy group, a 2-methylbutoxygroup, a hexyloxy group, or an isohexyloxy group.

In the present invention, a “C₃-C₆ cycloalkoxy group” refers to a groupin which a C₃-C₆ cycloalkyl group mentioned above is substituted by anoxy group, and is a cyclopropoxy group, a cyclobutoxy group, acyclopentyloxy group, or a cyclohexyloxy group.

In the present invention, a “C₃-C₄ cycloalkoxy group” is a cyclopropoxygroup or a cyclobutoxy group.

In the present invention, a “C₃-C₈ cycloalkoxy group” is a cyclopropoxygroup, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxygroup, a cycloheptyloxy group, or a cyclooctyloxy group.

In the present invention, a “C₁-C₆ alkylthio group” refers to a group inwhich a C₁-C₆ alkyl group mentioned above is substituted by a thiogroup. Examples thereof include a methylthio group, an ethylthio group,a propylthio group, and an isopropylthio group.

In the present invention, a “C₁-C₆ alkylsulfonyl group” refers to agroup in which a C₁-C₆ alkyl group mentioned above is substituted by asulfonyl group. Examples thereof include a methylsulfonyl group, anethylsulfonyl group, a propylsulfonyl group, and an isopropylsulfonylgroup.

In the present invention, a “C₁-C₆ alkylsulfonylamide group” refers to agroup in which a C₁-C₆ alkylsulfonyl group mentioned above issubstituted by an amino group. Examples thereof include amethylsulfonylamide group, an ethylsulfonylamide group, apropylsulfonylamide group, and an isopropylsulfonylamide group.

In the present invention, a “C₁-C₆ alkylcarbonyl group” refers to agroup in which a C₁-C₆ alkyl group mentioned above is substituted by acarbonyl group. Examples thereof include an acetyl group, anethylcarbonyl group, a propylcarbonyl group, and an isopropylcarbonylgroup.

In the present invention, a “C₁-C₆ alkoxycarbonyl group” refers to agroup in which a C₁-C₆ alkoxy group mentioned above is substituted by acarbonyl group. Examples thereof include a methoxycarbonyl group, anethoxycarbonyl group, a propoxycarbonyl group, and an isopropoxycarbonylgroup.

In the present invention, a “C₃-C₆ cycloalkylcarbonyl group” refers to agroup in which a C₃-C₆ cycloalkyl group mentioned above is substitutedby a carbonyl group, and is a cyclopropylcarbonyl group, acyclobutylcarbonyl group, a cyclopentylcarbonyl group, or acyclohexylcarbonyl group.

In the present invention, a “C₃-C₆ cycloalkoxycarbonyl group” refers toa group in which a C₃-C₆ cycloalkoxy group mentioned above issubstituted by a carbonyl group, and is a cyclopropoxycarbonyl group, acyclobutoxycarbonyl group, a cyclopentyloxycarbonyl group, or acyclohexyloxycarbonyl group.

In the present invention, a “C₁-C₆ alkylamino group” refers to a groupin which a C₁-C₆ alkyl group mentioned above is substituted by an aminogroup. Examples thereof include a methylamino group, an ethylaminogroup, a propylamino group, and an isopropylamino group.

In the present invention, a “di-C₁-C₆ alkylamino group” refers to agroup in which two identical or different C₁-C₆ alkyl groups mentionedabove are substituted by an amino group. Examples thereof include adimethylamino group, a diethylamino group, a dipropylamino group, and adiisopropylamino group.

In the present invention, a “C₁-C₆ alkylaminocarbonyl group” refers to agroup in which a C₁-C₆ alkylamino group mentioned above is substitutedby a carbonyl group. Examples thereof include a methylaminocarbonylgroup, an ethylaminocarbonyl group, a propylaminocarbonyl group, and anisopropylaminocarbonyl group.

In the present invention, a “C₃-C₆ cycloalkylaminocarbonyl group” refersto a group in which a C₃-C₆ cycloalkyl group mentioned above is bondedto the amino group side of a (—NH—C(═O)—) group, and is acyclopropylaminocarbonyl group, a cyclobutylaminocarbonyl group, acyclopentylaminocarbonyl group, or a cyclohexylaminocarbonyl group.

In the present invention, a “C₃-C₈ cycloalkylamino group” refers to agroup in which a C₃-C₈ cycloalkyl group mentioned above is bonded to anamino group, and is a cyclopropylamino group, a cyclobutylamino group,or a cyclopentylamino group.

In the present invention, a “C₂-C₆ alkenyloxy group” refers to a groupin which a linear or branched C₂-C₆ alkenyl group having 2 to 6 carbonatoms is bonded to an oxy group. Examples thereof include a vinyloxygroup, an allyloxy group, and an isopropenyloxy group.

In the present invention, a “C₃-C₆ cycloalkenyl group” is acyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, or acyclohexenyl group.

In the present invention, a “5- or 6-membered heteroaryl group” refersto a group derived from a 5- or 6-membered monocyclic aromatic compoundcontaining 1 to 3 atoms each independently selected from the groupconsisting of a nitrogen atom, an oxygen atom and a sulfur atom inaddition to carbon as atoms constituting the ring. Examples thereofinclude a furyl group, a thienyl group, a pyrrolyl group, an oxazolylgroup, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, animidazolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group,a pyrimidinyl group, and a pyridazinyl group.

In the present invention, a “3- to 6-membered saturated heterocyclicgroup” refers to a group derived from a 3- to 6-membered monocyclicsaturated heterocyclic compound containing one atom selected from thegroup consisting of a nitrogen atom, an oxygen atom and a sulfur atom inaddition to carbon as atoms constituting the ring. Examples thereofinclude an aziridinyl group, an oxiranyl group, a thiiranyl group, anazetidinyl group, an oxetanyl group, a thietanyl group, a pyrrolidinylgroup, a tetrahydrofuranyl group, a tetrahydrothienyl group, apiperidinyl group, a tetrahydropyranyl group, and atetrahydrothiopyranyl group.

In the present invention, an “asymmetric catalyst” refers to a catalystfor use in asymmetric synthesis. Examples thereof include catalystshaving a metal atom therein.

In the present invention, a “Lewis acid” refers to a substance capableof accepting an electron pair. Examples thereof include Zn(OTf)₂, AgOAc,Cu(OTf)₂, CuOAc, Ni(OAc)₂, Co(OAc)₂, CuCl, CuBr, CuI, CuPF₆, CuBF₄,Cu(OAc)₂, Cu(OTf)₂, and CuSO₄.

In the present invention, a “chiral ligand” refers to a substance havingasymmetry and capable of forming a coordinate bond with a metal andincludes not only unidentate ligands but multidentate ligands. Examplesthereof include BINAP derivatives, MeBIPHEP derivatives, TunePHOSderivatives, P-Phos derivatives, JOSIPHOS derivatives, Walphosderivatives, FESULPHOS derivatives, Taniaphos derivatives, Jospophosderivatives, FOXAP derivatives, Mandyphos derivatives, Ferrocelanederivatives, PHOX derivatives, and QuinoxP derivatives.

In the present invention, the phrase “having asymmetry” means having anasymmetric center, axial chirality, or planar chirality.

In the present invention, the symbol “*” means an asymmetric center oraxial chirality.

In the present invention, the symbol “Cy” is an abbreviation of acyclopentyl group.

In the present invention, a “ketimine” refers to an imine formed from aketone and an amine and is a compound having a structure in which thecarbonyl group of the ketone is substituted by the nitrogen atom of theamine.

A compound represented by formula (I), a compound represented by formula(II), a compound represented by formula (III), a compound represented byformula (IV) or a salt thereof, a compound represented by formula (V), acompound represented by formula (VI), a compound represented by formula(VII), a compound represented by formula (VIII), a compound representedby formula (IX), a compound represented by formula (X), a compoundrepresented by formula (XI), a compound represented by formula (XII), acompound represented by formula (XIII) or a salt thereof, a compoundrepresented by formula (XIV) or a salt thereof, a compound representedby formula (XV) or a salt thereof, a compound represented by formula(XVI), a compound represented by formula (XVII), a compound representedby formula (XVIII), a compound represented by formula (XIX) or a saltthereof, a compound represented by formula (XX), a compound representedby formula (XXI) or a salt thereof, and a compound represented byformula (XXII) or a salt thereof according to the present inventionencompass all isomers (diastereomers, optical isomers, geometricisomers, rotational isomers, etc.)

In the compound represented by formula (I), the compound represented byformula (II), the compound represented by formula (III), the compoundrepresented by formula (IV) or a salt thereof, the compound representedby formula (V), the compound represented by formula (VI), the compoundrepresented by formula (VII), the compound represented by formula(VIII), the compound represented by formula (IX), the compoundrepresented by formula (X), the compound represented by formula (XI),the compound represented by formula (XII), the compound represented byformula (XIII) or a salt thereof, the compound represented by formula(XIV) or a salt thereof, the compound represented by formula (XV) or asalt thereof, the compound represented by formula (XVI), the compoundrepresented by formula (XVII), the compound represented by formula(XVIII), the compound represented by formula (XIX) or a salt thereof,the compound represented by formula (XX), the compound represented bygeneral formula (XXI) or a salt thereof, and the compound represented byformula (XXII) or a salt thereof, their isomers and mixtures of theseisomers are all represented by single formulae. Thus, the presentinvention includes all of these isomers and mixtures of these isomers inarbitrary ratios.

A compound represented by formula (IV), a compound represented byformula (XIII), a compound represented by formula (XIV), a compoundrepresented by formula (XV), a compound represented by formula (XIX), acompound represented by formula (XXI), and a compound represented byformula (XXII) according to the present invention may each be convertedinto a salt through its reaction with an acid when having a basic groupor through its reaction with a base when having an acidic group.

Examples of a salt based on a basic group can include: hydrohalides suchas hydrofluoride, hydrochloride, hydrobromide, and hydroiodide;inorganic acid salts such as nitrate, perchlorate, sulfate, andphosphate; C₁-C₆ alkylsulfonates such as methanesulfonate,trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such asbenzenesulfonate and p-toluenesulfonate; and carboxylates such asacetate, oxalate, tartrate, and maleate.

On the other hand, examples of a salt based on an acidic group caninclude: alkali metal salts such as sodium salt, potassium salt, andlithium salt; alkaline earth metal salts such as calcium salt andmagnesium salt; metal salts such as aluminum salt and iron salt;inorganic salts such as ammonium salt; amine salts of organic salts,etc., such as t-octylamine salt, dibenzylamine salt, morpholine salt,glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt,N-methylglucamine salt, guanidine salt, diethylamine salt, triethylaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt,chloroprocaine salt, procaine salt, diethanolamine salt,N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt,and tris(hydroxymethyl)aminomethane salt; and amino acid salts such asglycine salt, lysine salt, arginine salt, ornithine salt, glutamate, andaspartate.

A compound represented by formula (IV) or a salt thereof, a compoundrepresented by formula (XIII) or a salt thereof, a compound representedby formula (XIV) or a salt thereof, a compound represented by formula(XV) or a salt thereof, a compound represented by formula (XIX) or asalt thereof, a compound represented by formula (XXI) or a salt thereof,and a compound represented by formula (XXII) or a salt thereof accordingto the present invention, when left in air or recrystallized, may eachincorporate a water molecule to form a hydrate. Such a hydrate is alsoincluded in a salt of the present invention.

A compound represented by formula (IV) or a salt thereof, a compoundrepresented by formula (XIII) or a salt thereof, a compound representedby formula (XIV) or a salt thereof, a compound represented by formula(XV) or a salt thereof, a compound represented by formula (XIX) or asalt thereof, a compound represented by formula (XXI) or a salt thereof,and a compound represented by formula (XXII) or a salt thereof accordingto the present invention, when left in a solvent or recrystallized, mayeach absorb a certain kind of solvent to form a solvate. Such a solvateis also included in a salt of the present invention.

Examples of a solvent include: ether solvents such as tetrahydrofuranand 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, and2-propanol; hydrocarbon solvents such as toluene; nitrile solvents suchas acetonitrile; aliphatic ester solvents such as ethyl acetate; andamide solvents such as N,N-dimethylacetamide and N,N-dimethylformamide.

Next, preferred embodiments of the present invention will be described.

Preferred forms of each substituent in a compound represented by formula(I), a compound represented by formula (II), a compound represented byformula (III), a compound represented by formula (IV), a compoundrepresented by formula (V), a compound represented by formula (XIII), acompound represented by formula (XIV), and a compound represented byformula (XV) are given below.

R¹ represents a hydrogen atom, a C₁-C₆ alkylcarbonyl group, or a C₁-C₆alkoxycarbonyl group optionally having one phenyl group. R¹ is morepreferably a hydrogen atom, an acetyl group, a t-butoxycarbonyl group,or a benzyloxycarbonyl group, further preferably a hydrogen atom.

R² represents a 5- or 6-membered heteroaryl group having, in the ring, 1to 3 heteroatoms independently selected from the group consisting of anitrogen atom, an oxygen atom and a sulfur atom, or a phenyl group,wherein the 5- or 6-membered heteroaryl group and the phenyl group eachoptionally have 1 to 3 substituents independently selected from thegroup consisting of a halogen atom, a hydroxy group, an amino group, anaminocarbonyl group, and a C₁-C₆ alkyl group.

R² is more preferably a phenyl group optionally having 1 to 3 halogenatoms, or a pyridyl group optionally having 1 to 3 halogen atoms, evenmore preferably a phenyl group having one fluorine atom and one chlorineatom, or a pyridyl group having one fluorine atom and one chlorine atom.

Ring Z is a benzene ring optionally having 1 to 4 halogen atoms and ismore preferably a benzene ring having one chlorine atom.

R³ and R⁴ each independently represent a C₁-C₆ alkyl group optionallyhaving 1 to 3 substituents independently selected from the groupconsisting of a halogen atom, a hydroxy group, and an amino group. BothR³ and R⁴ are more preferably the same C₁-C₆ alkyl groups, even morepreferably methyl groups.

In another form of R³ and R⁴, preferably, R³ and R⁴ together form aC₄-C₆ cycloalkyl ring optionally having 1 to 3 C₁-C₆ alkyl groups on thering, a piperidine ring optionally having 1 to 3 C₁-C₆ alkyl groups onthe ring, or a tetrahydropyran ring optionally having 1 to 3 C₁-C₆ alkylgroups on the ring. The ring formed is more preferably a cyclopentanering optionally having 1 to 3 C₁-C₆ alkyl groups on the ring, acyclohexane ring optionally having 1 to 3 C₁-C₆ alkyl groups on thering, or a tetrahydropyran ring optionally having 1 to 3 C₁-C₆ alkylgroups on the ring, even more preferably a 4,4-dimethylcyclohexane ring.

R⁵ represents a C₁-C₆ alkoxy group, a C₃-C₈ cycloalkoxy group, a C₂-C₆alkenyloxy group, a C₁-C₆ alkylamino group, a C₃-C₈ cycloalkylaminogroup, or a tetrahydropyranylamino group. R⁵ is more preferably a C₁-C₆alkoxy group or a tetrahydropyranylamino group, even more preferably aC₁-C₆ alkoxy group.

R²² and R²³ each independently represent a hydrogen atom, a C₁-C₆ alkylgroup optionally having 1 to 3 substituents independently selected fromgroup I below, a C₁-C₆ alkylsulfonyl group optionally having 1 to 3substituents independently selected from group I below, a C₃-C₆cycloalkyl group optionally having 1 to 3 substituents independentlyselected from group I below, an azetidinyl group optionally having 1 to3 substituents independently selected from group I below, a pyrrolidinylgroup optionally having 1 to 3 substituents independently selected fromgroup I below, a piperidinyl group optionally having 1 to 3 substituentsindependently selected from group I below, a piperazinyl groupoptionally having 1 to 3 substituents independently selected from groupI below, a morpholino group optionally having 1 to 3 substituentsindependently selected from group I below, a phenyl group optionallyhaving 1 to 3 substituents independently selected from group I below, apyridyl group optionally having 1 to 3 substituents independentlyselected from group I below, a pyrimidinyl group optionally having 1 to3 substituents independently selected from group I below, a pyridazinylgroup optionally having 1 to 3 substituents independently selected fromgroup I below, a pyrrolyl group optionally having 1 to 3 substituentsindependently selected from group I below, a pyrazolyl group optionallyhaving 1 to 3 substituents independently selected from group I below, animidazolyl group optionally having 1 to 3 substituents independentlyselected from group I below, an oxazolyl group optionally having 1 to 3substituents independently selected from group I below, an oxadiazolylgroup optionally having 1 to 3 substituents independently selected fromgroup I below, or a triazolyl group optionally having 1 to 3substituents independently selected from group I below:

group I: a halogen atom, a hydroxy group, an oxo group, a carboxy group,a formyl group, an amino group, an aminocarbonyl group, a cyano group, aC₁-C₆ alkylamino group, a C₁-C₆ alkylsulfonyl group, a C₁-C₆alkylsulfonylamide group, a C₁-C₆ alkyl group optionally having 1 to 3substituents independently selected from group J below, a C₁-C₆ alkoxygroup optionally having 1 to 3 substituents independently selected fromgroup J below, a C₁-C₆ alkylcarbonyl group optionally having 1 to 3substituents independently selected from group J below, a C₃-C₆cycloalkylcarbonyl group optionally having 1 to 3 substituentsindependently selected from group J below, a C₄-C₆ cycloalkyl groupoptionally having 1 to 3 substituents independently selected from groupJ below, a C₁-C₆ alkoxycarbonyl group optionally having 1 to 3substituents independently selected from group J below, a piperidinylgroup optionally having 1 to 3 substituents independently selected fromgroup J below, a pyrrolidinyl group optionally having 1 to 3substituents independently selected from group J below, a piperazinylgroup optionally having 1 to 3 substituents independently selected fromgroup J below, a phenyl group optionally having 1 to 3 substituentsindependently selected from group J below, a tetrazolyl group, anazetidinyl group optionally having 1 to 3 substituents independentlyselected from group J below, a morpholinyl group optionally having 1 to3 substituents independently selected from group J below, adihydropyrazolyl group optionally having 1 to 3 substituentsindependently selected from group J below, and an oxadiazolyl group:group J: a halogen atom, a hydroxy group, an amino group, a carboxygroup, an aminocarbonyl group, a phenyl group, a C₁-C₆ alkyl group, aC₁-C₆ alkylamino group, a di-C₁-C₆ alkylamino group, a C₁-C₆alkylcarbonyl group, a C₃-C₆ cycloalkyl group, a C₁-C₆ alkylsulfonylgroup, and a C₁-C₆ alkylsulfonylamide group.

R²² and R²³ are, more preferably, each independently a hydrogen atom, amethyl group, a methylsulfonyl group, or any of the following T¹ to T³⁵:

M is a nitrogen atom or CH and is more preferably a nitrogen atom.

L is CH₂ or C(CH₃)₂ and is more preferably C(CH₃)₂.

R⁵³ is a C₁-C₆ alkyl group.

In a preferred combination of the substituents in the compoundrepresented by the formula (I), R¹ is a hydrogen atom, R² is a phenylgroup having one fluorine atom and one chlorine atom, and ring Z is abenzene ring having one chlorine atom.

In a preferred combination of the substituents in the compoundrepresented by formula (V), R³ and R⁴ together form a4,4-dimethylcyclohexane ring, and R⁵ is a C₁-C₆ alkoxy group.

In a preferred combination of the substituents in the compoundrepresented by formula (IV) or the compound represented by formula(XIII) in the present invention, R¹ is a hydrogen atom, R² is a phenylgroup having one fluorine atom and one chlorine atom, ring Z is abenzene ring having one chlorine atom, R³ and R⁴ together form a4,4-dimethylcyclohexane ring, and R⁵ is a C₁-C₆ alkoxy group.

In a preferred combination of the substituents in the compoundrepresented by formula (XIV), R¹ is a hydrogen atom, R² is a phenylgroup having one fluorine atom and one chlorine atom, ring Z is abenzene ring having one chlorine atom, and R³ and R⁴ together form a4,4-dimethylcyclohexane ring.

In a preferred combination of the substituents in the compoundrepresented by formula (XV), R¹ is a hydrogen atom, R² is a phenyl grouphaving one fluorine atom and one chlorine atom, ring Z is a benzene ringhaving one chlorine atom, R³ and R⁴ together form a4,4-dimethylcyclohexane ring, and each of R²² and R²³ is T²⁴ mentionedabove.

In a preferred combination of the substituents in the compoundrepresented by formula (XIX), M is a nitrogen atom, L is C(CH₃)₂, andR⁵³ is a C₁-C₆ alkyl group.

In a preferred combination of the substituents in the compoundrepresented by formula (XX), L is C(CH₃)₂, and R⁵³ is a C₁-C₆ alkylgroup.

In a preferred combination of the substituents in the compoundrepresented by formula (XXI) or the compound represented by formula(XXII), M is a nitrogen atom, and L is C(CH₃)₂.

Next, preferred compounds of the compound represented by formula (VI),the compound represented by formula (VII), the compound represented byformula (VIII), the compound represented by formula (IX), the compoundrepresented by formula (X), the compound represented by formula (XI),and the compound represented by formula (XII) will be described.

The compound represented by formula (VI) is a BINAP derivative and ispreferably a compound represented by any of the following formulae:

more preferably a compound represented by any of the following formulae:

The compound represented by formula (VII) is a MeBIOPHEP derivative, aP-Phos derivative, or a TunePHOS derivative and is preferably a compoundrepresented by any of the following formulae:

more preferably a compound represented by any of the following formulae:

The compound represented by formula (VIII) is a JOSIPHOS derivative, aWalphos derivative, a FESULPHOS derivative, a Taniaphos derivative, aJospophos derivative, or a FOXAP derivative and is preferably a compoundrepresented by any of the following formulas:

more preferably a compound represented by any of the following formulae:

The compound represented by formula (IX) is a Mandyphos derivative andis preferably a compound represented by any of the following formulae:

The compound represented by formula (X) is a Ferrocelane derivative andis preferably a compound represented by any of the following formula:

The compound represented by formula (XI) is a PHOX derivative and ispreferably a compound represented by any of the following formulae:

The compound represented by formula (XII) is a QuinoxP derivative and ispreferably a compound represented by the following formula:

In the present invention, the Lewis acid is CuOAc, CuCl, CuBr, CuI,CuOTf, CuPF₆, CuBF₄, Cu(OAc)₂, Cu(OTf)₂, or CuSO₄ and is more preferablyCuOAc or Cu(OAc)₂.

In the present invention, a preferred combination of the Lewis acid andthe chiral ligand is CuOAc or Cu(OAc)₂ as the Lewis acid and a compoundrepresented by any of the following formulae as the chiral ligand:

In the present invention, the solvent is preferably one or two selectedfrom the group consisting of N,N-dimethylacetamide, tetrahydrofuran,dimethoxyethane, 2-propanol, toluene, and ethyl acetate, more preferablyone or two selected from the group consisting of N,N-dimethylacetamideand ethyl acetate. Alternatively, a mixture of the solvents in anarbitrary ratio may be used.

Next, the present invention will be described. It should be understoodthat the reaction conditions of the present invention are not limited tothose described herein. In the present invention, a functional group ina compound may be protected with an appropriate protective group.Examples of such a functional group can include a hydroxy group, acarboxy group, and an amino group. For the type of protective group andconditions for the introduction and removal of the protective group, seethose described in, for example, Protective Groups in Organic Synthesis(T. W. Greene and P. G. M. Wuts, John Wiley & Sons, Inc., New York,2006).

[Production Method]

1) Method for producing a compound represented by formula (IV)

A compound represented by formula (IV) is obtained by reacting acompound represented by formula (I), a compound represented by formula(II), and a compound represented by formula (III) in the presence of anasymmetric catalyst prepared from a Lewis acid and a chiral ligand, anda solvent. Also, the compound represented by formula (IV) can beobtained by forming in advance a compound represented by formula (V)(ketimine) from a compound represented by formula (II) and a compoundrepresented by formula (III) and then reacting the ketimine with acompound represented by formula (I).

The reaction is preferably carried out in the presence of a base.

A compound represented by the formula (I) can be produced according tovarious references (e.g., WO2006/091646 and WO2012/121361).

The amount of the compound represented by formula (II) used is in therange of 0.5 equivalents to 10 equivalents with respect to the compoundrepresented by formula (I) and is preferably in the range of 1.0equivalent to 3.0 equivalents with respect to the compound representedby formula (I).

The amount of the compound represented by formula (III) used is in therange of 0.5 equivalents to 10 equivalents with respect to the compoundrepresented by formula (I) and is preferably in the range of 1.0equivalent to 3.0 equivalents with respect to the compound representedby formula (I).

Examples of the Lewis acid that can be used include a Zn(II) Lewis acid,a Ag(I) Lewis acid, a Ni(II) Lewis acid, a Co(II) Lewis acid, a Ru(I)Lewis acid, a Cu(I) Lewis acid, and a Cu(II) Lewis acid. The Lewis acidis preferably CuOAc, CuCl, CuBr, CuI, CuOTf, CuPF₆, CuBF₄, Cu(OAc)₂,Cu(OTf)₂, or CuSO₄.

As for the amounts of the Lewis acid and the chiral ligand used, theligand is preferably added in the range of 0.8 to 3.0 equivalents withrespect to the Lewis acid and in the range of 0.01 to 100 mol % of theLewis acid with respect to the compound represented by formula (I). Morepreferably, the ligand is added in the range of 1.01 to 2.4 equivalentswith respect to the Lewis acid and in the range of 0.5 to 20 mol % ofthe Lewis acid with respect to the compound (I).

Examples of the chiral ligand that can be used include BINAPderivatives, MeBIPHEP derivatives, TunePHOS derivatives, P-Phosderivatives, JOSIPHOS derivatives, Walphos derivatives, FESULPHOSderivatives, Taniaphos derivatives, Jospophos derivatives, FOXAPderivatives, Mandyphos derivatives, Ferrocelane derivatives, PHOXderivatives, and QuinoxP derivatives. The chiral ligand is preferably aBINAP derivative, a Tunephos derivative, a MeBIPHEP derivative, a P-Phosderivative, a JOSIPHOS derivative, a FOXAP derivative, a FESULPHOSderivative, or the like.

The chiral ligand can be purchased from, for example, Sigma-AldrichInc., Tokyo Chemical Industry Co., Ltd., Wako Pure Chemical Industries,Ltd., or Strem Chemicals Inc.

Examples of the base that can be used include: tertiary amines such astriethylamine and N,N-diisopropylethylamine; organic bases such assodium ethoxide and t-butoxy potassium; and inorganic bases such assodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate,potassium hydroxide, potassium carbonate, potassium bicarbonate, andpotassium acetate. The base is preferably a tertiary amine such astriethylamine or N,N-diisopropylethylamine, more preferablytriethylamine.

The amount of the base used is in the range of 0.01 equivalents to 10equivalents with respect to the compound represented by formula (I) andis preferably in the range of 0.01 equivalents to 0.2 equivalents withrespect to the compound represented by formula (I).

Examples of the solvent include: ether solvents such as tetrahydrofuranand 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, and2-propanol; hydrocarbon solvents such as toluene; nitrile solvents suchas acetonitrile; aliphatic ester solvents such as ethyl acetate; andamide solvents such as N,N-dimethylacetamide and N,N-dimethylformamide.These solvents can be used alone or as a mixture in an arbitrary ratio.Preferably, ether solvents such as tetrahydrofuran, amide solvents suchas N,N-dimethylacetamide, and aliphatic ester solvents such as ethylacetate are preferably used alone or as a mixture in an arbitrary ratio.

The amount of the solvent used is in the range of 1 to 100 times theamount of the compound (I) and is preferably in the range of 5 to 50times the amount of the compound represented by formula (I), morepreferably in the range of 8 to 25 times the amount of the compoundrepresented by formula (I).

The reaction temperature is in the range of −88° C. to the boiling pointof the solvent used and is preferably in the range of −20° C. to 60° C.

The reaction time is in the range of 30 minutes to 96 hours and ispreferably in the range of 30 minutes to 64 hours, more preferably inthe range of 30 minutes to 48 hours.

2) Method for Producing a Compound Represented by Formula (XIV)

A compound represented by formula (XIV) is obtained by hydrolyzing acompound represented by formula (IV) (provided that R⁵ is not —NR⁵¹R⁵²).

The hydrolysis can be carried out by the addition of a base or an acidin a solvent.

Examples of the base that can be used include: organic bases such assodium ethoxide and t-butoxy potassium; and inorganic bases such assodium hydroxide, lithium hydroxide, sodium carbonate, potassiumhydroxide, and potassium carbonate. The base is preferably an inorganicbase such as sodium hydroxide, lithium hydroxide, or potassiumhydroxide, more preferably sodium hydroxide.

The amount of the base used is in the range of 1 equivalent to 10equivalents with respect to the compound represented by formula (IV) andis preferably in the range of 1 equivalent to 5 equivalents with respectto the compound represented by formula (IV), more preferably in therange of 1 equivalent to 3 equivalents with respect to the compoundrepresented by formula (IV).

Examples of the acid include: hydrohalic acids such as hydrofluoricacid, hydrochloric acid, hydrobromic acid, and hydroiodic acid;inorganic acids such as nitric acid, perchloric acid, sulfuric acid, andphosphoric acid; C₁-C₆ alkylsulfonic acids such as methanesulfonic acid,trifluoromethanesulfonic acid, and ethanesulfonic acid; arylsulfonicacids such as benzenesulfonic acid and p-toluenesulfonic acid; andcarboxylic acids such as acetic acid, trifluoroacetic acid, oxalic acid,tartaric acid, and maleic acid. The acid is preferably trifluoroaceticacid or hydrochloric acid.

The amount of the acid used is in the range of 1 equivalent to 100equivalents with respect to the compound represented by formula (IV) andis preferably in the range of 1 equivalent to 10 equivalents withrespect to the compound represented by formula (IV).

Examples of the solvent include: ether solvents such as tetrahydrofuranand 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, and2-propanol; hydrocarbon solvents such as toluene; nitrile solvents suchas acetonitrile; aliphatic ester solvents such as ethyl acetate; amidesolvents such as N,N-dimethylacetamide and N,N-dimethylformamide; andhalogen solvents such as dichloromethane and chloroform. These solventscan be used alone or as a mixture at an arbitrary ratio. The solvent ispreferably a halogen solvent such as dichloromethane, an alcohol solventsuch as methanol, or a mixed solvent of an ether solvent such astetrahydrofuran and an alcohol solvent such as methanol.

The amount of the solvent used is in the range of 1 to 100 times theamount of the compound represented by formula (IV) and is preferably inthe range of 5 to 50 times the amount of the compound represented byformula (IV), more preferably in the range of 8 to 25 times the amountof the compound represented by formula (IV).

The reaction temperature is in the range of −88° C. to the boiling pointof the solvent used and is preferably in the range of −20° C. to 60° C.

The reaction time is in the range of 30 minutes to 96 hours and ispreferably in the range of 30 minutes to 64 hours, more preferably inthe range of 30 minutes to 48 hours.

3) Method for Producing a Compound Represented by Formula (XV)

A compound represented by formula (XV) is obtained by condensing acompound represented by formula (XIV) with an amine NHR²²R²³ using acondensing agent in a solvent. The amine can be produced according tovarious references (e.g., WO2006/091646 and WO2012/121361).

The amount of the amine used is in the range of 0.5 equivalents to 10equivalents with respect to the compound represented by formula (XIV)and is preferably in the range of 1.0 equivalent to 2.0 equivalents withrespect to the compound represented by formula (XIV).

Examples of the condensing agent include: azodicarboxylic acid di-loweralkyl ester-triphenylphosphines such as azodicarboxylic acid diethylester-triphenylphosphine; carbodiimide derivatives such asN,N′-dicyclohexylcarbodiimide (DCC) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); 2-halo-1-loweralkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide;diarylphosphorylazides such as diphenylphosphorylazide (DPPA);phosphoryl chlorides such as diethylphosphoryl chloride; imidazolederivatives such as N,N′-carbodiimidazole (CDI); benzotriazolederivatives such as benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP),0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), and(1H-benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP); and triazine derivatives such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DM-TMM). The condensing agent is preferably1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),(1H-benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP), diphenylphosphorylazide (DPPA), or4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DM-TMM).

The amount of the condensing agent used is in the range of 1 equivalentto 10 equivalents with respect to the compound represented by formula(XIV) and is preferably in the range of 1 equivalent to 5 equivalentswith respect to the compound represented by formula (XIV), morepreferably in the range of 1 equivalent to 2 equivalents with respect tothe compound represented by formula (XIV).

Examples of the solvent that can be used include: ether solvents such astetrahydrofuran and 1,2-dimethoxyethane; alcohol solvents such asmethanol, ethanol, and 2-propanol; hydrocarbon solvents such as toluene;nitrile solvents such as acetonitrile; aliphatic ester solvents such asethyl acetate; and amide solvents such as N,N-dimethylacetamide andN,N-dimethylformamide. The solvent is preferably an amide solvent suchas N,N-dimethylacetamide.

The amount of the solvent used is in the range of 1 to 100 times theamount of the compound represented by formula (XIV) and is preferably inthe range of 3 to 50 times the amount of the compound represented byformula (XIV), more preferably in the range of 5 to 25 times the amountof the compound represented by formula (XIV).

The reaction temperature is in the range of −88° C. to the boiling pointof the solvent used and is preferably in the range of −20° C. to 60° C.

The reaction time is in the range of 30 minutes to 96 hours and ispreferably in the range of 30 minutes to 64 hours, more preferably inthe range of 30 minutes to 48 hours.

EXAMPLES

Hereinafter, the present invention will be described in more detail withreference to Examples. However, the scope of the present invention isnot intended to be limited by them.

Abbreviations used in the Examples are as defined below. mg: milligram,g: gram, ml: milliliter, L: liter, MHz: megahertz.

In the Examples below, nuclear magnetic resonance (hereinafter, referredto as 1H NMR; 500 MHz) spectra were indicated by the 8 value (ppm) ofchemical shift with tetramethylsilane as a standard. As for splitpatterns, s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet,and br: broad. In the present Examples, “UHPLC” or“ultrahigh-performance liquid chromatography” was performed usingProminence UFLC (Shimadzu Corp.).

Example 1 Ethyl(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate

To a mixture of(3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one(WO2006/091646) (99.9 mg, 0.32 mmol), (R)-BINAP (12.1 mg, 0.019 mmol),and CuOAc (2.0 mg, 0.016 mmol), a solution of cyclohexanone (50.4 μL,0.49 mmol), glycine ethyl ester (39.6 LL, 0.39 mmol) and triethylamine(6.8 μL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL) was added under anitrogen atmosphere, and the resulting mixture was stirred at roomtemperature for 40 hours. To the reaction mixture, ethyl acetate (2 mL),water (1 mL), and a 20% aqueous ammonium chloride solution (1 mL) wereadded, and the mixture was vigorously stirred to separate an organiclayer. The aqueous layer was subjected to extraction with ethyl acetatetwice (2 mL each), and the organic layers were all combined and thenwashed with water three times (5 mL each). The organic layer obtainedwas concentrated under reduced pressure. To the residue, ethyl acetate(6 mL) and silica gel (500 mg) were added, and the silica gel wasfiltered off. The filtrate was concentrated under reduced pressure. Tothe residue, ethanol (1.25 mL) was added, then water (1 mL) was addeddropwise, and the mixture was stirred overnight at room temperature. Thedeposited solid was filtered and dried under reduced pressure at 40° C.to obtain the title compound (102.9 mg, yield: 65%, 91% ee) as a solid.

¹H NMR (500 MHz, CDCl₃): δ=0.91-1.60 (m, 2H), 1.17 (t, J=7.3 Hz, 3H),1.38-1.74 (m, 6H), 1.87-2.0 (m, 1H), 2.12-2.20 (m, 1H), 3.19 (s, 1H),4.07-4.20 (m, 2H), 4.54 (d, J=9.0 Hz, 1H), 4.84 (d, J=9.0 Hz, 1H), 6.73(d, J=2.0 Hz, 1H), 6.83-6.89 (m, 1H), 7.05 (dd, J=8.3, 1.8 Hz, 1H),7.10-7.16 (m, 1H), 7.36 (dd, J=8.0, 2.0 Hz, 1H), 7.49-7.55 (m, 1H), 7.65(s, 1H).

(Conditions for High-Performance Liquid Chromatography (HPLC) forOptical Purity Measurement)

Column: CHIRALPAK IC 4.6×250 mm, 5 μm

Mobile phase: 10 mM AcOH buffer:MeCN=40:60

Flow rate: 1.0 min/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Injection quantity: 5 μL

Retention time: title compound=14.1 min, enantiomer=11.4 min

Example 2 Ethyl(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate

To a mixture of(3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one(WO2006/091646) (98.7 mg), (R)-BINAP (12.1 mg, 0.019 mmol), and CuOAc(2.0 mg, 0.016 mmol), a solution of 4,4-dimethlcyclohexanone (61.4 mg,0.48 mmol), glycine ethyl ester (39.5 LL, 0.39 mmol) and triethylamine(6.8 μL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL) was added under anitrogen atmosphere, and the resulting mixture was stirred at roomtemperature for 22 hours. To the reaction mixture, ethyl acetate (2 mL),water (1 mL), and a 20% aqueous ammonium chloride solution (1 mL) wereadded, and the mixture was vigorously stirred to separate an organiclayer. The aqueous layer was subjected to extraction with ethyl acetatetwice (2 mL each), and the organic layers were all combined and thenwashed with water three times (5 mL each). The organic layer obtainedwas concentrated under reduced pressure. To the residue, ethyl acetate(6 mL) and silica gel (500 mg) were added, and the silica gel wasfiltered off. The filtrate was concentrated under reduced pressure. Tothe residue, ethanol (1.0 mL) was added, then water (1 mL) was addeddropwise, and the mixture was stirred overnight at room temperature. Thedeposited solid was filtered and dried under reduced pressure at 40° C.to obtain the title compound (137 mg, yield: 82%, 94% ee) as a solid.

¹H NMR (500 MHz, CDCl₃): δ=0.67 (s, 3H), 0.91 (s, 3H), 1.10-1.19 (m,2H), 1.17 (t, J=7.3 Hz, 3H), 1.25-1.33 (m, 1H), 1.44-1.72 (m, 3H),1.87-2.01 (m, 1H), 3.16 (s, 1H), 4.07-4.21 (m, 2H), 4.52 (d, J=8.5 Hz,1H), 4.83 (d, J=8.5 Hz, 1H), 6.74 (d, J=1.5 Hz, 1H), 6.81-6.86 (m, 1H),7.06 (dd, J=8.3, 2.8 Hz, 1H), 7.10-7.16 (m, 1H), 7.37 (dd, J=8.3, 1.8Hz, 1H), 7.48-7.54 (m, 1H), 7.81 (s, 1H).

(Conditions for HPLC for Optical Purity Measurement)

Column: CHIRALPAK OD-3R 4.6×150 mm, 3 μm

Mobile phase: 10 mM phosphate buffer:MeCN=40:60

Flow rate: 1.0 min/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Injection quantity: 5 μL

Retention time: title compound=13.8 min, enantiomer=12.9 min

Example 3 Ethyl(3′R,4′S,5′R)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate

To a mixture of(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one(WO2012/121361) (99.2 mg), (R)-BINAP (12.1 mg, 0.019 mmol), and CuOAc(2.0 mg, 0.016 mmol), a solution of cyclohexanone (50.4 μL, 0.49 mmol),glycine ethyl ester (39.6 μL, 0.39 mmol), and triethylamine (6.8 μL,0.049 mmol) in N,N-dimethylacetamide (2.0 mL) was added under a nitrogenatmosphere, and the resulting mixture was stirred at 0° C. for 18 hours.To the reaction mixture, ethyl acetate (2 mL), water (1 mL), and a 20%aqueous ammonium chloride solution (1 mL) were added, and the mixturewas vigorously stirred to separate an organic layer. The aqueous layerwas subjected to extraction with ethyl acetate twice (2 mL each), andthe organic layers were all combined and then washed with water threetimes (5 mL each). The organic layer obtained was concentrated underreduced pressure, and the residue was purified by silica gelchromatography [heptane:ethyl acetate=1:1 (v/v)]. To the residueobtained, ethanol (1.0 mL) was added, then water (1 mL) was addeddropwise, and the mixture was stirred overnight at room temperature. Thedeposited solid was filtered and dried under reduced pressure at 40° C.to obtain the title compound (101.2 mg, yield: 64%, 99% ee) as a solid.

¹H NMR (500 MHz, CDCl₃): δ=0.9-1.1 (m, 2H), 1.19 (t, J=7.3 Hz, 3H), 1.44(td, J=12.9, 3.2 Hz, 1H) m, 1.48-1.70 (m, 1H), 3.2 (s, 1H), 4.12-4.20(m, 2H), 4.53 (d, J=9.0 Hz, 1H), 4.82 (d, J=10.0 Hz, 1H), 6.77 (d, J=2.0Hz, 1H), 7.07 (dd, J=8.0, 1.5 Hz, 1H), 7.34 (dd, J=8.3, 1.8 Hz, 1H),7.5-7.56 (m, 1H), 7.59 (s, 1H), 8.06 (d, J=5.0 Hz, 1H).

(Conditions for HPLC for Optical Purity Measurement)

Column: CHIRALPAK OD-3R 4.6×150 mm, 3 μm

Mobile phase: 10 mM phosphate buffer:MeCN=40:60

Flow rate: 1.0 min/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Injection quantity: 5 μL

Retention time: title compound=7.7 min, enantiomer=8.7 min

Example 4 Ethyl(3′R,4′S,5′R)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate

To a mixture of(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one(WO2012/121361) (100.7 mg), (R)-BINAP (12.1 mg, 0.019 mmol), and CuOAc(2.0 mg, 0.016 mmol), a solution of 4,4-dimethylcyclohexanone (61.4 mg,0.48 mmol), glycine ethyl ester (39.5 μL, 0.39 mmol), and triethylamine(6.8 μL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL) was added under anitrogen atmosphere, and the resulting mixture was stirred at 0° C. for14 hours. To the reaction mixture, ethyl acetate (2 mL), water (1 mL),and a 20% aqueous ammonium chloride solution (1 mL) were added, and themixture was vigorously stirred to separate an organic layer. The aqueouslayer was subjected to extraction with ethyl acetate twice (2 mL each),and the organic layers were all combined and then washed with waterthree times (5 mL each). The organic layer obtained was concentratedunder reduced pressure. To the residue, ethyl acetate (6 mL) and silicagel (500 mg) were added, and the silica gel was filtered off. Thefiltrate was concentrated under reduced pressure. To the residue,ethanol (1.0 mL) was added, then water (1 mL) was added dropwise, andthe mixture was stirred overnight at room temperature. The depositedsolid was filtered and dried under reduced pressure at 40° C. to obtainthe title compound (134.9 mg, yield: 80%, 99% ee) as a solid.

1H NMR (500 MHz, CDCl₃): δ=0.67 (s, 3H), 0.91 (s, 3H), 1.11-1.21 (m,2H), 1.19 (t, J=7.0 Hz, 3H), 1.24-1.34 (m, 1H), 1.43-1.58 (m, 2H),1.60-1.72 (m, 1H), 1.85-1.95 (m, 1H), 3.19 (s, 1H), 4.10-4.21 (m, 2H),4.51 (d, J=9.0 Hz, 1H), 4.82 (d, J=9.5 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H),7.07 (dd, J=8.5, 1.5 Hz, 1H), 7.36 (dd, J=8.3, 1.8 Hz, 1H), 7.5-7.55 (m,1H), 7.68 (bs, 1H), 8.05 (d, J=5.5 Hz, 1H).

(Conditions for HPLC for Optical Purity Measurement)

Column: CHIRALPAK OD-3R 4.6×150 mm, 3 μm

Mobile phase: 10 mM phosphate buffer:MeCN=40:60

Flow rate: 1.0 min/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Injection quantity: 5 μL

Retention time: title compound=9.4 min, enantiomer=10.5 min

Example 5 Ethyl(3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluorophenyl)-3′,3′-dimethyl-2-oxo-1,2-dihydrospiro[indole-3,3′-pyrrolidine]-5′-carboxylate

To a mixture of(3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one(WO2006/091646) (50.8 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), andCuOAc (1.0 mg, 0.008 mmol), a solution of acetone (23.8 μL, 0.32 mmol),glycine ethyl ester (26.4 LL, 0.26 mmol), and triethylamine (3.4 LL,0.024 mmol) in N,N-dimethylacetamide (1.0 mL) was added under a nitrogenatmosphere, and the resulting mixture was stirred at 0° C. for 42 hours.To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20%aqueous ammonium chloride solution (0.5 mL) were added, and the mixturewas vigorously stirred to separate an organic layer. The aqueous layerwas subjected to extraction with ethyl acetate twice (1 mL each), andthe organic layers were all combined and then washed with water threetimes (2.5 mL each). The organic layer obtained was concentrated underreduced pressure, and the residue was purified by silica gelchromatography [heptane:ethyl acetate:triethylamine=50:50:1 (v/v)] anddried under reduced pressure at 40° C. to obtain a mixture of the titlecompound and diastereomers (66.8 mg, yield: 90%, diastereomer ratio: 84(title compound):13:3, optical purity of the title compound: 92% ee) asan oil compound.

¹H NMR (500 MHz, CDCl₃): δ=1.07 (s, 3H), 1.17 (t, J=7.0 Hz, 3H), 1.48(s, 3H), 3.40-3.62 (m, 1H), 4.07-4.23 (m, 2H), 4.55 (d, J=9.0 Hz, 1H),4.91 (d, J=9.5 Hz, 1H), 6.75-6.80 (m, 1H), 6.80 (d, J=1.5 Hz, 1H), 7.06(dd, J=8.0, 2.0 Hz, 1H), 7.09-7.15 (m, 1H), 7.38 (dd, J=8.3, 2.3 Hz,1H), 7.45-7.50 (m, 1H), 8.62 (s, 1H).

(Conditions for HPLC for Optical Purity Measurement)

Column: CHIRALPAK IC 4.6×250 mm, 5 μm

Mobile phase: 0.1% HCOOH aq.:MeCN=70:30

Flow rate: 1.0 min/min

Column temperature: 27° C.

Detection wavelength: 254 nm

Injection quantity: 5 μL

Retention time: title compound=10.3 min, enantiomer=11.1 min

Example 6 Ethyl(3′R,4′S,5′R)-6-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-2-oxo-1,2-dihydrodispiro[indole-3,3′-pyrrolidine-2′,4″-pyran]-5′-carboxylate

To a mixture of(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one(WO2012/121361) (48.7 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), andCuOAc (1.0 mg, 0.008 mmol), a solution of tetrahydro-4H-pyran-4-one(22.4 μL, 0.24 mmol), glycine ethyl ester (20 μL, 0.20 mmol), andtriethylamine (3.4 LL, 0.024 mmol) in N,N-dimethylacetamide (1.0 mL) wasadded under a nitrogen atmosphere, and the resulting mixture was stirredat 0° C. for 42 hours. To the reaction mixture, ethyl acetate (1 mL),water (0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL)were added, and the mixture was vigorously stirred to separate anorganic layer. The aqueous layer was subjected to extraction with ethylacetate twice (1 mL each), and the organic layers were all combined andthen washed with water three times (2.5 mL each). The organic layerobtained was concentrated under reduced pressure, and the residue waspurified by silica gel chromatography [heptane:ethylacetate:triethylamine=50:50:1 (v/v)] and dried under reduced pressure at40° C. to obtain a mixture of the title compound and diastereomers (74.9mg, yield: 96%, diastereomer ratio: 75 (title compound):20:5, opticalpurity of the title compound: 98% ee) as an oil compound.

¹H NMR (500 MHz, CDCl₃): δ=1.19 (t, J=7.3 Hz, 3H), 1.31-1.41 (m, 1H),1.42-1.50 (m, 1H), 1.85-1.98 (m, 2H), 3.18-3.38 (m, 1H), 3.67-3.77 (m,2H), 3.84-3.92 (m, 1H), 3.88-4.06 (m, 1H), 4.08-4.20 (m, 2H), 4.56 (d,J=9.5 Hz, 1H), 4.78 (d, J=9.5 Hz, 1H), 6.79 (d, J=2.5 Hz, 1H), 7.08 (dd,J=8.3, 1.8 Hz, 1H), 7.34 (dd, J=8.3, 2.3 Hz, 1H), 7.49-7.54 (m, 1H),8.06 (d, J=5.0 Hz, 1H), 8.43 (s, 1H).

(Conditions for HPLC for optical purity measurement)

Column: CHIRALPAK IC 4.6×250 mm, 5 μm

Mobile phase: 10 mM AcOH buffer:MeCN=40:60

Flow rate: 1.0 min/min

Column temperature: 27° C.

Detection wavelength: 220 nm

Injection quantity: 5 μL

Retention time: title compound=26.2 min, enantiomer=22.8 min

Example 7 Ethyl(3′R,4′S,5′R)-6-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-3′,3′-dimethyl-2-oxo-1,2-dihydrospiro[indole-3,3′-pyrrolidine]-5′-carboxylate

To a mixture of(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one(WO2012/121361) (51 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), andCuOAc (1.0 mg, 0.008 mmol), a solution of acetone (17.8 μL, 0.24 mmol),glycine ethyl ester (20 μL, 0.20 mmol), and triethylamine (3.4 μL, 0.024mmol) in N,N-dimethylacetamide (1.0 mL) was added under a nitrogenatmosphere, and the resulting mixture was stirred at 0° C. for 42 hours.To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20%aqueous ammonium chloride solution (0.5 mL) were added, and the mixturewas vigorously stirred to separate an organic layer. The aqueous layerwas subjected to extraction with ethyl acetate twice (1 mL each), andthe organic layers were all combined and then washed with water threetimes (2.5 mL each). The organic layer obtained was concentrated underreduced pressure, and the residue was purified by silica gelchromatography [heptane:ethyl acetate:triethylamine=50:50:1 (v/v)] anddried under reduced pressure at 40° C. to obtain a mixture of the titlecompound and diastereomers (68.9 mg, yield: 92%, diastereomer ratio: 87(title compound):13, optical purity of the title compound: 98% ee) as anoil compound.

1H NMR (500 MHz, CDCl₃): δ=1.08 (s, 3H), 1.20 (t, J=7.0 Hz, 3H), 1.46(s, 3H), 3.40-3.65 (m, 1H), 4.09-4.26 (m, 2H), 4.54 (d, J=9.5 Hz, 1H),4.89 (d, J=9.0 Hz, 1H), 6.79 (d, J=1.5 Hz, 1H), 7.07 (dd, J=8.5, 2.0 Hz,1H), 7.36 (dd, J=8.0, 1.5 Hz, 1H), 7.49-7.55 (m, 1H), 7.86 (s, 1H), 8.07(d, J=5.0 Hz, 1H).

(Conditions for HPLC for Optical Purity Measurement)

Column: CHIRALPAK AS-RH 4.6×150 mm, 5 μm

Mobile phase: 10 mM AcOH buffer:MeCN=60:40

Flow rate: 1.0 min/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Injection quantity: 5 μL

Retention time: title compound=8.4 min, enantiomer=7.1 min

Example 8 Ethyl(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-2″-oxo-1″,2″-dihydrodispiro[cyclopentane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate

To a mixture of(3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one(WO2006/091646) (52.1 mg, 0.17 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), andCuOAc (1.0 mg, 0.008 mmol), a solution of cyclopentanone (28.7 μL, 0.32mmol), glycine ethyl ester (26.4 LL, 0.26 mmol), and triethylamine (3.4μL, 0.024 mmol) in N,N-dimethylacetamide (1.0 mL) was added under anitrogen atmosphere, and the resulting mixture was stirred at 0° C. for42 hours. To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL),and a 20% aqueous ammonium chloride solution (0.5 mL) were added, andthe mixture was vigorously stirred to separate an organic layer. Theaqueous layer was subjected to extraction with ethyl acetate twice (1 mLeach), and the organic layers were all combined and then washed withwater three times (2.5 mL each). The organic layer obtained wasconcentrated under reduced pressure, and the residue was purified bysilica gel chromatography [heptane:ethylacetate:triethylamine=100:50:1.5 (v/v)] and dried under reduced pressureat 40° C. to obtain a mixture of the title compound and diastereomers(69 mg, yield: 86%, diastereomer ratio: 84 (title compound):14:2,optical purity of the title compound: 99% ee) as an oil compound.

1H NMR (500 MHz, CDCl₃): δ=1.17 (t, J=7.3 Hz, 3H), 1.22-1.30 (m, 1H),1.32-1.42 (m, 1H), 1.50-1.60 (m, 2H), 1.66-1.83 (m, 2H), 1.86-1.97 (m,1H), 2.07-2.15 (m, 1H), 3.25-3.64 (m, 1H), 4.07-4.23 (m, 2H), 4.53 (d,J=9.5 Hz, 1H), 4.76 (d, J=9.0 Hz, 1H), 6.72-6.77 (m, 1H), 6.80 (d, J=2.0Hz, 1H), 7.06 (dd, J=8.0, 1.5 Hz, 1H), 7.08-7.13 (m, 1H), 7.38 (dd,J=8.0, 2.0 Hz, 1H), 7.43-7.50 (m, 1H), 8.68 (s, 1H).

(Conditions for HPLC for Optical Purity Measurement)

Column: CHIRALPAK IC 4.6×250 mm, 5 μm

Mobile phase: 0.1% HCOOH aq.:MeCN=50:50

Flow rate: 1.0 min/min

Column temperature: 27° C.

Detection wavelength: 220 nm

Injection quantity: 5 μL

Retention time: title compound=6.0 min, enantiomer=5.6 min

Example 9 Ethyl(3′R,4′S,5′R)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-2″-oxo-1″,2″-dihydrodispiro[cyclopentane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate

To a mixture of(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one(WO2012/121361) (50.9 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), andCuOAc (1.0 mg, 0.008 mmol), a solution of cyclopentanone (21.6 μL, 0.24mmol), glycine ethyl ester (20 μL, 0.20 mmol), and triethylamine (3.4LL, 0.024 mmol) in N,N-dimethylacetamide (1.0 mL) was added under anitrogen atmosphere, and the resulting mixture was stirred at 0° C. for42 hours. To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL),and a 20% aqueous ammonium chloride solution (0.5 mL) were added, andthe mixture was vigorously stirred to separate an organic layer. Theaqueous layer was subjected to extraction with ethyl acetate twice (1 mLeach), and the organic layers were all combined and then washed withwater three times (2.5 mL each). The organic layer obtained wasconcentrated under reduced pressure, and the residue was purified bysilica gel chromatography [heptane:ethyl acetate:triethylamine=50:50:1(v/v)] and dried under reduced pressure at 40° C. to obtain a mixture ofthe title compound and diastereomers (69.1 mg, yield: 88%, diastereomerratio: 87 (title compound):13, optical purity of the title compound: 98%ee) as an oil compound.

1H NMR (500 MHz, CDCl₃): δ=1.19 (t, J=7.3 Hz, 3H), 1.22-1.30 (m, 1H),1.32-1.43 (m, 1H), 1.48-1.60 (m, 2H), 1.66-1.82 (m, 2H), 1.86-1.96 (m,1H), 2.02-2.09 (m, 1H), 3.40-3.62 (m, 1H), 4.08-4.24 (m, 2H), 4.53 (d,J=9.0 Hz, 1H), 4.73 (d, J=9.0 Hz, 1H), 6.82 (d, J=1.5 Hz, 1H), 7.07 (dd,J=8.3, 1.8 Hz, 1H), 7.36 (dd, J=8.3, 2.3 Hz, 1H), 7.50-7.54 (m, 1H),8.04 (d, J=5.5 Hz, 1H), 8.60 (s, 1H).

(Conditions for HPLC for Optical Purity Measurement)

Column: CHIRALPAK IC 4.6×250 mm, 5 μm

Mobile phase: 0.1% HCOOH aq.:MeCN=50:50

Flow rate: 1.0 min/min

Column temperature: 27° C.

Detection wavelength: 220 nm

Injection quantity: 5 μL

Retention time: title compound=6.7 min, enantiomer=13.3 min

Example 10(3′R,4′S,5′R)—N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide

Step 1(4′S,5′R)-6″-Chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylicAcid

To a solution of the compound (5.00 g, 9.61 mmol) obtained in Example 4in methanol (25 mL) and tetrahydrofuran (25 mL), a 1 N aqueous sodiumhydroxide solution (18.3 mL, 18.3 mmol) was added under ice cooling, andthe mixture was stirred at 0° C. for 41.5 hours. The reaction mixturewas neutralized to pH 3 by the addition of concentrated hydrochloricacid under ice cooling. Water (75 mL) was added dropwise thereto, andthe mixture was then stirred at room temperature for 4 hours. Thedeposited solid was filtered at 0° C. and dried under reduced pressureat 40° C. to obtain the title compound (4.52 g, yield: 96%) as a solid.

Step 2(3′R,4′S,5′R)—N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide

To a solution of the compound (2.00 g, 4.06 mmol) obtained in thepreceding step 1 in N,N-dimethylacetamide (20 mL),1-hydroxybenzotriazole monohydrate (310 mg, 2.02 mmol),(2S,5R)-5-aminotetrahydro-2H-pyran-2-carboxamide (WO2012/121361) (707mg, 4.90 mmol), diisopropylethylamine (850 LL, 4.88 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (934 mg,4.87 mmol) were added, and the mixture was stirred at 0° C. for 47.5hours. To the reaction mixture, ethyl acetate (20 mL) and water (10 mL)were added, and the mixture was stirred to separate an organic layer.The aqueous layer was subjected to extraction with ethyl acetate twice(20 mL each), and the organic layers were all combined and then washedwith water three times (20 mL each). The solvent was distilled off underreduced pressure. To the residue, acetonitrile (30 mL) was then added,and the mixture was stirred at 60° C. for 2 hours. The reaction mixturewas allowed to cool, and the deposited solid was then filtered and driedunder reduced pressure at 40° C. to obtain the title compound (2.13 g,yield: 80%) as a solid.

Example 11

11-1) Influence of Various Asymmetric Catalysts

To a solution of(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one(WO2012/121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethylester (1.2 eq.), and triethylamine (15 mol %) in THF (10-fold amount), acatalyst solution separately prepared by stirring a Lewis acid (5 mol%), a chiral ligand (6 mol %), and THF (10-fold amount) for 1 hour undera nitrogen atmosphere was added under a nitrogen atmosphere, and themixture was stirred at room temperature for 12 to 16 hours. Then, theoptical purity and HPLC yield of the obtained trans-1 compound ((ethyl(3′S,4′R,5′S)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate)were measured by HPLC.

(Conditions for HPLC for Optical Purity Measurement)

Column: CHIRALPAK OD-3R 4.6×150 mm, 3 μm

Mobile phase: 10 mM phosphate buffer:MeCN=40:60

Flow rate: 1.0 min/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Injection quantity: 5 μL

Retention time: title compound=13.8 min, enantiomer=12.9 min

Main results are shown in Table 1

TABLE 1 Lewis acid AgOAc Cu(OTf)₂ CuOAc ee % No. Ligand (ee %) (ee %)(yield %) 1

31.9 34.1 88.0 (76.8) 2

34.9 36.6 88.8 (76.3) 3

32.1 18.7 76.2 4

19.1 45.8 72.6 5

51.6 29.4 89.0 (74.2) 6

26.0 27.9 72.5 7

48.9 — 86.9 (76.3) 8

32.9 — 43.911-2) Influence of Various Solvents

To(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one(WO2012/121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethylester (1.2 eq.), triethylamine (15 mol %), and a solvent (10-foldamount), a catalyst solution separately prepared by stirring CuOAc (5mol %), (S)-BINAP (6 mol %), and a solvent (10-fold amount) for 1 hourunder a nitrogen atmosphere was added under a nitrogen atmosphere, andthe mixture was stirred at room temperature for 21.5 hours. Then, theHPLC yield and optical purity of the obtained trans-2 compound (ethyl(3′S,4′R,5′S)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate)were measured by HPLC.

Main results are shown in Table 2.

TABLE 2 No. Solvent HPLC yield (%) ee (%) trans/cis 1 THF 78.7 91.392/8  2 MeOH — 66.2 84/16 3 EtOH — 72.8 86/14 4 IPA — 83.8 85/15 5toluene — 87.5 9/1 6 MeCN — 56.4 86/14 7 DMAc 85.2 97.1 94/6  8 DME 85.593.4 93/7  9 AcOEt — 88.7 92/8 11-3) Study on Cu(I) Lewis Acid

To(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one(WO2012/121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethylester (1.2 eq.), triethylamine (15 mol %), and N,N-dimethylacetamide(10-fold amount), a catalyst solution separately prepared by stirringCu(I) Lewis acid (5 mol %), (S)-BINAP (6 mol %), andN,N-dimethylacetamide (10-fold amount) for 1 hour under a nitrogenatmosphere was added under a nitrogen atmosphere, and the mixture wasstirred at room temperature for 17 to 21.5 hours. Then, the HPLC yieldand optical purity of the obtained trans-2 compound (ethyl(3′S,4′R,5′S)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate)were measured by HPLC.

Main results are shown in Table 3.

TABLE 3 No. Lewis Acid HPLC yield (%) ee (%) trans/cis 1 CuOAc 85.2 97.194/6 2 CuCl 38.2 52.8  87/13 3 CuBr 55.9 76.4 92/8 4 CuI 72.9 89 94/6 5Cu₂O 25.4 23.5  83/17 6 (CuOTf)₂ toluene 84.1 95 93/7 7 Cu(CH₃CN)₄PF₆88.6 95.9 95/5 8 Cu(CH₃CN)₄BF₄ 89.1 95.8 94/611-4) Study on Cu(II) Lewis Acid

(3E/Z)-6-Chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one(WO2012/121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethylester (1.2 eq.), Cu(II) Lewis acid (5 mol %), (R)-BINAP (6 mol %), andN,N-dimethylacetamide (20-fold amount) were stirred at room temperaturefor 15 hours under a nitrogen atmosphere. Then, the UPLC yield andoptical purity of the obtained trans-2 compound (ethyl(3′R,4′S,5′R)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate)were measured by UPLC and HPLC, respectively.

Main results are shown in Table 4.

TABLE 4 No. Lewis Acid HPLC yield (%) ee (%) trans/cis 1 Cu(OAc)₂•H₂O79.4 97.1 95/5  2 Cu(OTf)₂ 58.5 88.5 92/8  3 CuSO₄•5H₂O 53.4 83.1 92/8 4 CuO 14.3 −13.3 49/51 5 CuCl₂ 17.8 −6.7 72/28 6 CuBr₂ 19.0 −3.3 74/26 7CuCO₃•Cu(OH)₂•H₂O 13.8 −15.8 74/26 * Sign “−” in the column “ee”indicates that the trans-2 compound (ethyl(3′S,4′R,5′S)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate)was a main product.11-5) Study Using CuOAc and Various Chiral Ligands

To a solution of(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one(WO2012/121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethylester (1.2 eq.), and triethylamine (15 mol %) in THF (10-fold amount), acatalyst solution separately prepared by stirring CuOAc (5 mol %), achiral ligand (6 mol %), and THF (10-fold amount) for 1 hour under anitrogen atmosphere was added under a nitrogen atmosphere, and themixture was stirred at room temperature for 12 to 16 hours. Then, theyield and optical purity of the obtained trans-1 compound (ethyl(3′S,4′R,5′S)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate)were measured by HPLC.

Main results are shown in Table 5.

TABLE 5 No. Ligand ee % Yield %  1

88.0 76.8  2

88.8 76.3  3

76.2 —  4

72.6 —  5

89.0 74.2  6

72.5 —  7

91.4 79.2  8

90.2 76.9  9

76.1 — 10

59.9 — 11

51.4 — 12

91.9 78.0 13

−54.1 — 14

53.0 — 15

86.9 76.3 16

−85.9 71.0 17

−94.6 73.7 18

−86.2 75.5 *: Sign “—” in the column “ee” indicates that the trans-2compound (ethyl(3′S,4′R,5′S)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate)was a main product.

Example 12 tert-Butyl(3′R,4′S,5′R)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate

To a mixture of(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one(WO2012/121361) (50.0 mg, 0.16 mmol), (R)-BINAP (6.0 mg, 0.009 mmol),and CuOAc (1.0 mg, 0.008 mmol), a solution of 4,4-dimethylcyclohexanone(31.0 mg, 0.25 mmol), glycine tert-butyl ester (27.8 mg, 0.21 mmol), andtriethylamine (3.4 μl, 0.024 mmol) in N,N-dimethylacetamide (1.0 ml) wasadded under a nitrogen atmosphere, and the resulting mixture was stirredat 0° C. for 19.5 hours. To the reaction mixture, ethyl acetate (2.0ml), water (0.5 ml), and a 20% aqueous ammonium chloride solution (0.5ml) were added, and the mixture was vigorously stirred to separate anorganic layer. The aqueous layer was subjected to extraction with ethylacetate twice (2.0 ml each), and the organic layers were all combinedand then washed with water three times (2.0 ml each). The organic layerobtained was concentrated under reduced pressure, and the residue waspurified by silica gel chromatography [heptane:ethylacetate:triethylamine=50:50:1 (v/v)] and dried under reduced pressure at40° C. to obtain a mixture of the title compound and a diastereomer(61.0 mg, yield: 69%, diastereomer ratio: 90 (title compound):10,optical purity of the title compound: 97% ee) as an oil compound.

1H NMR (500 MHz, CDCl₃): δ=0.67 (s, 3H), 0.92 (s, 3H), 1.10-1.25 (m,3H), 1.33 (s, 9H), 1.45-1.75 (m, 3H), 1.80-2.00 (m, 2H), 3.15-3.20 (m,1H), 4.42 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.5 Hz, 1H), 6.77 (d, J=2.0 Hz,1H), 7.06 (dd, J=8.3, 1.8 Hz, 1H), 7.34 (dd, J=8.5, 2.0 Hz, 1H),7.53-7.63 (m, 2H), 8.06 (d, J=5.0 Hz, 1H)

(Conditions for HPLC for Optical Purity Measurement)

Column: CHIRALPAK OD-3R 4.6×150 mm, 3 μm

Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN=50:50

Flow rate: 1.0 ml/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Injection quantity: 5 μl

Retention time: title compound=9.4 min, enantiomer=11.4 min

Reference Example 1(2S,5R)-5-[(2-Aminoacetyl)amino]tetrahydro-2H-pyran-2-carboxamide

Step 1 tert-ButylN-(2-{[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]amino}-2-oxoethyl)carbamate

To a slurry of N-(tert-butoxycarbonyl)glycine (1.01 g, 5.77 mmol),(2S,5R)-5-aminotetrahydro-2H-pyran-2-carboxamide (WO2012/121361) (0.85g, 5.90 mmol), and diisopropylethylamine (994 μl, 5.71 mmol) intetrahydrofuran (40 ml),0-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluroniumhexafluorophosphate (2.21 g, 5.83 mmol) was added, and the mixture wasstirred at room temperature for 18 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel chromatography [ethyl acetate:methanol=98:2→80:20 (v/v)]. Tothe solid obtained, ethyl acetate (20 ml) was added, and the mixture wasstirred at room temperature for 4 hours. The slurry obtained wasfiltered and dried under reduced pressure at 40° C. to obtain the titlecompound (1.47 g, yield: 83%) as a white solid.

¹H NMR (500 MHz, CDCl₃): δ=1.40-1.50 (m, 1H), 1.46 (s, 9H), 1.57-1.66(m, 1H), 2.08-2.16 (m, 1H), 2.22-2.28 (m, 1H), 3.09 (t, J=10.5 Hz, 1H),3.70-3.82 (m, 3H), 3.90-4.02 (m, 1H), 4.16 (ddd, J=10.9, 4.9, 1.9 Hz,1H), 5.08-5.15 (m, 1H), 5.38-5.46 (m, 1H), 5.95-6.05 (m, 1H), 6.43-6.53(m, 1H)

Step 2 (2S,5R)-5-[(2-Aminoacetyl)amino]tetrahydro-2H-pyran-2-carboxamide

To the compound (500 mg, 1.66 mmol) obtained in the preceding step 1, asolution of 4 N hydrogen chloride in cyclopentyl methyl ether (5 ml, 20mmol) was added, and the mixture was stirred at room temperature for 15hours. The reaction mixture was filtered and washed with cyclopentylmethyl ether (5 ml). To a solution of the solid obtained in methanol (5ml), a solution of 28% sodium methoxide in methanol (810 μl, 3.32 mmol)was added, and the mixture was stirred at room temperature for 2 hours.To the reaction mixture obtained, neutral silica gel (500 mg) was added,and the mixture was concentrated under reduced pressure. To the residue,ethyl acetate (50 ml) and methanol (5 ml) were added, and the silica gelwas filtered off. The filtrate was concentrated under reduced pressure.To the residue, tetrahydrofuran (2.0 ml) was added, and the mixture wasstirred at room temperature for 17 hours. The slurry obtained wasfiltered and dried under reduced pressure at 40° C. to obtain the titlecompound (111 mg, yield: 33%) as a white solid.

¹H NMR (500 MHz, CD₃OD): δ=1.50-1.61 (m, 2H), 2.00-2.18 (m, 2H), 3.16(t, J=10.8 Hz, 1H), 3.21 (d, J=16.5 Hz, 1H), 3.25 (d, J=17.0 Hz, 1H),3.72-3.78 (m, 1H), 3.80-3.90 (m, 1H), 4.07 (ddd, J=10.9, 4.9, 1.9 Hz,1H)

Example 13(3′R,4′S,5′R)—N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide

To a mixture of the compound (39.1 mg, 0.19 mmol) obtained in ReferenceExample 1,(3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one(WO2006/091646) (48.6 mg, 0.16 mmol), (R)-BINAP (6.6 mg, 0.011 mmol),and CuOAc (1.2 mg, 0.010 mmol), a solution of 4,4-dimethylcyclohexanone(30.6 mg, 0.24 mmol) in N,N-dimethylacetamide (1.0 ml) was added under anitrogen atmosphere, and the resulting mixture was stirred at roomtemperature for 17 hours. The whole amount of the reaction mixture wasdiluted with methanol (100 ml) to obtain the title compound(ultrahigh-performance liquid chromatography (UHPLC) yield: 65%, 96% de)as a solution in methanol.

(Conditions for UHPLC Measurement for UHPLC Yield Calculation)

Column: CAPCELL CORE ADME 2.1×100 mm, 2.7 m

Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN

Gradient: MeCN 20%→92%

Gradient conditions: 0-2.5 min MeCN 20%, 2.5-7.3 min MeCN 20→92%, 7.3-14min MeCN 92%, 14.01-17 min MeCN 20%

Flow rate: 0.6 ml/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Injection quantity: 5 μl

Retention time: title compound=6.6 min

(Conditions for HPLC for De Measurement)

Column: CHIRALPAK OD-3R 4.6×150 mm, 3 μm

Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN=60:40

Flow rate: 1.0 ml/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Injection quantity: 10 μl

Retention time: title compound=17.7 min, diastereomer=8.5 min

Example 14(3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycyclohexyl)-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide

Step 1(4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycyclohexyl)-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5″-carboxylicAcid

To a slurry of the compound (1.00 g, 2.04 mmol) obtained in Example 1and methanol (10 ml), a 25% (w/v) aqueous sodium hydroxide solution (1.0ml, 6.25 mmol) was added under ice cooling, and the mixture was stirredat 0° C. for 27.5 hours. The reaction mixture was neutralized by theaddition of 35% (w/w) concentrated hydrochloric acid (651 mg, 6.25 mmol)under ice cooling. Water (15 ml) was added dropwise thereto, and themixture was then stirred at 0° C. for 18 hours. The deposited crystalswere filtered at 0° C. and dried under reduced pressure at 40° C. toobtain the title compound (0.90 g, yield: 95%, >99.5% ee) as a paleyellow solid.

¹H NMR (500 MHz, CD₃OD): δ=1.10-1.30 (m, 2H), 1.50-1.68 (m, 1H),1.70-2.13 (m, 5H), 2.18-2.28 (m, 1H), 2.50-2.62 (m, 1H), 4.81 (d, J=10.0Hz, 1H), 5.01 (d, J=10.0 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 7.07-7.15 (m,2H), 7.28-7.35 (m, 1H), 7.54 (dd, J=8.0, 2.5 Hz, 1H), 7.60-7.68 (m, 1H)

(Conditions for HPLC for Optical Purity Measurement)

Column: CHIRALPAK QN-AX 4.6×150 mm, 3 μm

Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN=60:40

Flow rate: 1.0 ml/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Injection quantity: 5 μl

Retention time: title compound=7.5 min, enantiomer=4.0 min

Step 2(3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycyclohexyl)-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide

To a solution of the compound (501 mg, 1.08 mmol, 99% ee) obtained inthe preceding step 1 and trans-4-aminocyclohexanol (157 mg, 1.36 mmol)in N,N-dimethylacetamide (5 ml),4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (392mg, 1.42 mmol) was added under ice cooling, and the mixture was stirredat 0° C. for 1 hour. To the reaction mixture, ethyl acetate (10 ml) andwater (5 ml) were added, and the mixture was stirred to separate anorganic layer. The aqueous layer was subjected to extraction with ethylacetate (10 ml), and the organic layers were all combined and thenwashed with water three times (10 ml each). The solvent was distilledoff under reduced pressure. To the residue, acetonitrile (15 ml) wasthen added, and the mixture was stirred at room temperature for 18hours. The deposited crystals were filtered and dried under reducedpressure at 40° C. to obtain the title compound (426 g, yield:70%, >99.5% ee) as a white solid.

¹H NMR (500 MHz, CD₃OD): δ=0.93 (td, J=13.5, 4.2 Hz, 1H), 1.0-1.15 (m,1H), 1.25-1.45 (m, 4H), 1.5-2.05 (m, 12H), 3.5-3.65 (m, 2H), 4.49 (d,J=9.5 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 6.71 (d, J=2.0 Hz, 1H), 7.02 (td,J=8.5, 2.0 Hz, 1H), 7.20 (td, J=15.0, 1.5 Hz, 1H), 7.39 (dd, J=8.5, 2.5Hz, 1H), 7.61 (td, J=14.8, 1.3 Hz, 1H)

(Conditions for HPLC for Optical Purity Measurement)

Column: CHIRALPAK OD-3R 4.6×150 mm, 3 μm

Mobile phase: 0.1% (v/v) HCOOH aq.:MeCN=60:40

Flow rate: 1.0 ml/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Injection quantity: 5 μl

Retention time: title compound=4.9 min, enantiomer=4.2 min

The invention claimed is:
 1. A method for producing a compound offormula (XXII) or a salt thereof comprising: hydrolyzing a compound offormula (XIX):

wherein R⁵³ is C₁-C₆ alkyl, to produce a compound of formula (XXI) or asalt thereof;

and condensing the compound of formula (XXI) or the salt thereof with acompound having the formula:

to produce a compound of formula (XXII) or a salt thereof:

wherein M is a nitrogen atom or CH; and L is a single bond, an oxygenatom, CH₂, or C(CH₃)₂.
 2. A method for producing a compound havingformula (XXII):

or a salt thereof, the method comprising: reacting a compound of formula(XVI):

a compound of formula (XVII):

and a compound of formula (XVIII):

in a solvent in the presence of a Lewis acid which is Cu(OAc) orCu(OAc)₂ and a chiral ligand selected from:

to stereoselectively produce a compound represented by formula (XIX) ora salt thereof,

hydrolyzing the compound of formula (XIX) to produce a compound offormula (XXI):

and condensing the compound of formula (XXI) with(1R,4R)-4-aminocyclohexane-1-carboxamide:

to produce the compound of formula (XXII); wherein M is N; L is C(CH₃)₂;and R⁵³ is C₁-C₆ alkyl.
 3. The method of claim 2, wherein the chiralligand has an (R) stereoconfiguration.
 4. The method of claim 3, whereinthe chiral ligand is (R)-BINAP.
 5. The method of claim 2, wherein theLewis acid is CuOAc.
 6. The method of claim 2, wherein R⁵³ is ethyl.